Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

BACKGROUND: Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC). OBJECTIVE: To study the clinical implications of TSG mRNA expression in mHSPC patients. DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSGlow status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSGwt for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis. RESULTS AND LIMITATIONS: A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSGlow (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSGlow was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSGlow patients, while a significant benefit was observed for ADT + D in the TSGwt group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART. CONCLUSIONS: TSGlow expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted. PATIENT SUMMARY: The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel.

(1) Background: Androgen deprivation therapy (ADT) and docetaxel (DX) combination is a standard therapy for metastatic hormone-sensitive prostate cancer (mHSPC) patients. (2) Methods: We investigate if tumor transcriptomic analysis predicts mHSPC evolution in a multicenter retrospective biomarker study. A customized panel of 184 genes was tested in mRNA from tumor samples by the nCounter platform in 125 mHSPC patients treated with ADT+DX. Gene expression was correlated with castration-resistant prostate cancer-free survival (CRPC-FS) and overall survival (OS). (3) Results: High expression of androgen receptor (AR) signature was independently associated with longer CRPC-FS (hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.3-0.9; p = 0.015), high expression of estrogen receptor (ESR) signature with longer CRPC-FS (HR 0.6, 95% CI 0.4-0.9; p = 0.019) and OS (HR 0.5, 95% CI 0.2-0.9, p = 0.024), and lower expression of tumor suppressor genes (TSG) (RB1, PTEN and TP53) with shorter OS (HR 2, 95% CI 1-3.8; p = 0.044). ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) Conclusions: AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus.

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Third-hand exposure at homes: Assessment using salivary cotinine.

BACKGROUND/OBJECTIVES: While exposure to secondhand smoke (SHS) is a well-established problem, exposure to third-hand smoke (THS) is scanty known and needs to be studied. The objective of this work is to characterize salivary cotinine concentrations among people who self-reported exposure to SHS and THS at home. METHODS: Cross-sectional study of a representative sample (n = 736) of the adult population (≥16 years) from the city of Barcelona carried out in 2013-2014. A questionnaire on tobacco use and passive exposure was administered, and a saliva sample was collected for cotinine determination. For this study, the information of the non-smoker participants who provided saliva sample (n = 519) was used. The geometric means (GM) and geometric standard deviations (GSD) of the cotinine concentration were compared according to the type of self-reported exposure at home: (1) Not exposed to SHS or THS; (2) Exposed to SHS and THS; and (3) Only exposed to THS. We used log-linear models to compare the cotinine concentration of each exposed group with respect to the unexposed group, adjusting for sex, age, educational level, and tobacco exposure in other settings. RESULTS: The GM of the salivary cotinine concentration was 0.34 ng/ml (GSD = 0.16) among individuals reporting SHS and THS exposure, 0.22 ng/ml (GSD = 0.15) among those reporting only THS exposure and 0.11 ng/ml (GSD = 0.04) among those who declared not to be exposed to SHS nor THS (p-value for trend <0.001). The regression model showed a statistically significant increase in cotinine concentration among those exposed to SHS and THS (188% higher, 95% CI: 153%; 223%), and only exposed to THS (106% higher, IC95. %: 74.5%; 137.0%) when comparing with the unexposed group. No statistically significant differences in cotinine concentration were observed between those exposed to SHS and THS compared to the THS group (-25.8%, 95% CI: -69.5%; 17.9%). CONCLUSIONS/RECOMMENDATIONS: People exposed to third-hand smoke at home had quantifiable cotinine levels in saliva. No differences in cotinine levels were found between those exposed to second-hand and third-hand smoke at home. The reduction of exposure to third-hand smoke at home should be put into the agenda of tobacco control.

Substance use during pregnancy and personality dimensions. / Consumo de substancias durante el embarazo y dimensiones de personalidad.

Our aim was to assess personality traits associated with substance use during pregnancy in a population-based, multicentre study of 1804 pregnant women. On day 2-3 postpartum, participants completed a semi-structured interview, including self-reported drug use (alcohol, tobacco, caffeine, cannabis, cocaine, opioids) during pregnancy, and socio-demographic, reproductive and obstetric variables, personal and family psychiatric history, social support, and the Eysenck personality questionnaire, short version (EPQ-RS). Logistic regression models were conducted. Fifty per cent of women reported substance use during pregnancy: 40% caffeine, 21% tobacco, 3.5% alcohol, and 0.3 % cannabis. Mean T-scores (SD) for personality dimensions were 51.1 (9.6) for extraversion, 48 (8.9) for psychoticism, and 43.6 (8.5) for neuroticism. Extroversion (p = .029) and psychoticism (p = .009) were identified as risk factors after adjustment by age, level of education, employment status during pregnancy, low social support, and previous psychiatric history. For each increment of 10 units in their scores, the odds of substance use increased by 12% and 16% respectively. Low education, being on leave during pregnancy, and previous psychiatric history were independent factors (p < .05) associated with substance use during pregnancy. Primiparity was a protective factor (p = .001). The final models showed a good fit (p = .26). The screening of substance use during pregnancy should include personality dimensions apart from psychosocial variables and history of psychiatric disorders. It is important to identify the associated risk factors for substance use during pregnancy to prevent and improve foetal/neonatal and maternal health during perinatal period.

Este estudio evalúa los patrones de consumo de substancias durante el embarazo y las dimensiones de personalidad asociadas, en una muestra multicéntrica de 1804 mujeres de población general. En el 2-3 día posparto, completaron una entrevista auto-administrada sobre el consumo de alcohol, tabaco, cafeína, cannabis, cocaína, opiáceos, drogas de diseño, además de variables socio-demográficas, obstétricas/reproductivas, historia psiquiátrica previa, apoyo social durante el embarazo y el cuestionario de personalidad de Eysenck (EPQ-RS). Se generaron modelos de regresión logística múltiple. La prevalencia del consumo fue del 50% (N=909): 40% cafeína, 21% tabaco, 3,5% alcohol, y 0,3 cannabis. Las puntuaciones T medias (DE) de personalidad fueron: extraversión 51,1 (9,6), psicoticismo 48 (8,9) y neuroticismo 43,6 (8,5). Las dimensiones de extraversión (p=0,029) y psicoticismo (p=0,009), fueron identificadas como factores de riesgo tras ajustar por edad, nivel educación, estatus laboral durante el embarazo, bajo apoyo social, e historia psiquiátrica previa. Para cada incremento de 10 unidades en sus puntuaciones, el odds de consumo de substancias durante el embarazo se incrementó un 12% y un 16% respectivamente. Menor educación, estar de baja, y antecedentes psiquiátricos fueron también factores independientes (p<0,05) asociados al consumo. Ser primípara fue factor protector (p=0,001). El modelo final mostró un ajuste satisfactorio (p=0,26). El cribaje de las mujeres con riesgo de consumo de substancias durante el embarazo debería incluir la personalidad además de variables psicosociales y antecedentes psiquiátricos. Identificar los factores de riesgo asociados es importante para prevenir y mejorar la salud materna y fetal/neonatal durante el embarazo y posparto.

Coping strategies for postpartum depression: a multi-centric study of 1626 women.

The transition to motherhood is stressful as it requires several important changes in family dynamics, finances, and working life, along with physical and psychological adjustments. This study aimed at determining whether some forms of coping might predict postpartum depressive symptomatology. A total of 1626 pregnant women participated in a multi-centric longitudinal study. Different evaluations were performed 8 and 32 weeks after delivery. Depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS) and the structured Diagnostic Interview for Genetic Studies (DIGS). The brief Coping Orientation for Problem Experiences (COPE) scale was used to measure coping strategies 2-3 days postpartum. Some coping strategies differentiate between women with and without postpartum depression. A logistic regression analysis was used to explore the relationships between the predictors of coping strategies and major depression (according to DSM-IV criteria). In this model, the predictor variables during the first 32 weeks were self-distraction (OR 1.18, 95 % CI 1.04-1.33), substance use (OR 0.58, 95 % CI 0.35-0.97), and self-blame (OR 1.18, 95 % CI 1.04-1.34). In healthy women with no psychiatric history, some passive coping strategies, both cognitive and behavioral, are predictors of depressive symptoms and postpartum depression and help differentiate between patients with and without depression.

Examining the factor structure and discriminant validity of the 12-item General Health Questionnaire (GHQ-12) among Spanish postpartum women.

In this study, the authors tested alternative factor models of the 12-item General Health Questionnaire (GHQ-12) in a sample of Spanish postpartum women, using confirmatory factor analysis. The authors report the results of modeling three different methods for scoring the GHQ-12 using estimation methods recommended for categorical and binary data. A discriminant function analysis was also performed to test the utility of a multiple factor model. A two-phase cross-sectional study was designed: (a) 1,453 women visiting at 6 weeks postpartum completed the GHQ-12 and the Edinburgh Postnatal Depression Scale questionnaire and (b) based on the Edinburgh Postnatal Depression Scale outcomes, participants were stratified and randomly selected within each stratum for clinical evaluation. Using the Likert-type scoring approach, Hankins's one-factor model with "method effects" obtained the best fit. In addition, Graetz's three-factor model provided little discrimination between diagnostic groups, the factors being highly correlated. These results support the presence of only one latent factor in the GHQ-12.

[Validation and comparison of four instruments to detect partner violence in health-care setting]. / Validación y comparación de cuatro instrumentos para la detección de la violencia de pareja en el ámbito sanitario.

BACKGROUND AND OBJECTIVES: To validate four instruments to detect domestic violence in health-care settings against external criteria -Index of Spouse Abuse (ISA), Psychological Maltreatment of Women Inventory short form (PMWI-SF), Woman Abuse Screening Tool (WAST), Partner Violence Screen (PVS)- and to assess the concordance and compare the diagnostic accuracy. SUBJECTS AND METHOD: This was a case-control study. The study sample was recruited from primary care and domestic violence centers. The ISA, PMWI-SF, WAST and PVS were administered to 223 controls and 182 intimate partner violence cases. Received Operating Characteristic (ROC) curve analysis was carried out. Measures were compared in terms of ROC curves and overall agreement. RESULTS: The areas under the curve (AUC) were: ISA 0.99 (IC 95%, 0.98-0.99), PMWI-SF 0.98 (IC 95% 0.97-0.99), WAST 0.95 (IC 95% 0.93-0.97), PVS 0.91 (IC 95% 0.87-0.94). The overall agreement between the four tools was excellent (Fleiss Kappa=0.82). The ISA and the PMWI-SF performed slightly better than WAST, and these three instruments performed better than PVS for detecting domestic violence. The PVS had lower concordance values with the other instruments. CONCLUSIONS: The four instruments demonstrated adequate diagnostic accuracy and overall agreement for detect domestic violence. Some overestimation of sensitivity may occur due to different source of cases.

Non-psychotic psychiatric disorders after childbirth: prevalence and comorbidity in a community sample.

BACKGROUND: Postnatal psychiatric morbidity is a frequent and serious complication of childbirth. The aim of the present study was to determine the prevalence and co-occurrence of DSM-IV psychiatric disorders in a community sample of postpartum Spanish mothers. METHODS: A two-phase cross-sectional study was conducted in which all consecutive women attending the routine 6-week postnatal control visit at the Department of Obstetric and Gynecology of a university-affiliated hospital over a one year period were included. In the first phase, 1453 women were screened with the Edinburgh Postnatal Depression Scale (EPDS). In the second phase, 428 participants stratified according to employment status and EPDS outcomes were randomly selected within each stratum for clinical psychiatric evaluation using the Structured Clinical Interview for DSM-IV. Weighted prevalence estimates were obtained for DSM-IV disorders with or without comorbidity. RESULTS: The overall 6-week prevalence rate for postpartum psychiatric disorders was 18.1% (95% CI 15.0-21.8) and 2.0% (95% CI 1.2-2.9) of postpartum women met criteria for more than one disorder. Mood disorders was the most prevalent group (9.8%; 95% CI 7.9-12.1) followed by adjustment disorders (4.3%; 95% CI 3.0-6.3), and anxiety disorders (4%; 95% CI 3.0-6.3). Comorbidity was associated to major depressive disorder. LIMITATIONS: Underestimation of some disorders due to the cross-sectional design and the use of a screening instrument with good psychometric characteristics restricted to depression, anxiety, and adjustment disorders. CONCLUSIONS: In the context of a 6-week postnatal visit, a high prevalence and heterogeneity of postnatal psychiatric morbidity in a community sample of Spanish women was found.

Postnatal psychiatric morbidity: a validation study of the GHQ-12 and the EPDS as screening tools.

OBJECTIVE: To assess the validity of the 12-Item General Health Questionnaire (GHQ-12) and the Edinburgh Postnatal Depression Scale (EPDS) in screening for the most common postnatal psychiatric morbidities (mood, anxiety and adjustment disorders). METHOD: A two-phase cross-sectional study was designed. First, a sample of 1453 women visiting at 6 weeks postpartum completed the GHQ-12 and the EPDS questionnaires. Second, based upon EPDS outcomes, participants were stratified and randomly selected within each stratum for clinical evaluation [Structured Clinical Interview for DSM-IV (SCID)]. Receiver operating characteristic (ROC) analysis was used. RESULTS: The concurrent validity was satisfactory (0.80). At optimum cut-off scores, both GHQ-12 and EPDS yielded very good sensitivity (80; 85.5) and specificity (80.4; 85.3), respectively. ROC curves showed that the performance of the EPDS (AUC=0.933) is slightly superior to that of GHQ-12 (AUC=0.904). CONCLUSION: Both GHQ-12 and EPDS are valid instruments to detect postnatal depression as well as postnatal anxiety and adjustment disorders.